KR20130049841A - 4-hydroxy tamoxifen gel formulations - Google Patents

Abstract

The present invention relates to pharmaceutical compositions containing 4-hydroxy tamoxifen, gels and methods of using the same.

Description

4-hydroxy tamoxifen gel formulations

The present invention relates to pharmaceutical compositions containing 4-hydroxy tamoxifen, gels and methods of use thereof.

Compound 4-hydroxy Tamoxifen (hereinafter referred to as 4-OHT) or 1- [4- (2-N-dimethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2-phenylbut-1 -N constitutes the active metabolite of tamoxifen, a well-characterized anti-estrogen compound. In the presence of a double bond between two carbon atoms, 4-hydroxy tamoxifen exists in two stereoisomeric forms. According to the medical and biochemical literature, the isomeric forms of 4-hydroxy tamoxifen are commonly referred to as cis and trans isomers. However, from a pure chemical point of view, since each double bonded carbon atom does not contain the same chemical group, such a name is not strictly speaking correct. Therefore, it is more appropriate to refer to the isomers as (E) (so-called cis form) and (Z) (so-called trans form) configuration.

In U.S. Patent No. 4,919,937, Mauveis-Jarvis et al. Disclose a 4-OTH formulation. However, such formulations do not contain a penetration enhancer and are specifically designed for the simultaneous administration of 4-OHT and progesterone.

There is a need for an improved 4-OTH containing formulation that is convenient for patients with good suitability, especially suitable for higher dose delivery, and that enables reproducible delivery of 4-OHT with improved safety profiles and appropriate systemic effects. There is also a need for 4-OHT topical formulations that allow the active ingredient to effectively penetrate through the skin.

The present invention provides pharmaceutical compositions, gels containing 4-OHT and methods of use thereof. More specifically, the present invention provides hydroalcoholic pharmaceutical compositions suitable for topical and transdermal administration containing from 0.105 to 0.950 weight percent of 4-hydroxy tamoxifen based on the total weight of the composition.

The composition of the present invention delivers 4-OHT very effectively, alone or in combination with other agents. In addition, the compositions of the present invention make it possible to have high patient suitability, in particular with respect to high dose delivery (eg, at least 1 mg of 4-OHT, preferably at least 2 mg of 4-OHT). Compositions of the present invention also exhibit suitable systemic exposure.

Accordingly, the present invention relates to pharmaceutical compositions comprising 4-OHT, at least one C2 to C6 alcohol, at least one gelling agent, at least one penetration enhancer, and an aqueous vehicle.

The pharmaceutical composition can be made into a variety of formulations, for example gels, solutions, creams, lotions, sprays, ointments, aerosols. Preferably the pharmaceutical composition is a gel and is suitable for topical administration.

As used herein, the term "4-OHT" (4-hydroxy tamoxifen) refers to 1- [4- (2-N-dimethylaminoethoxy) phenyl] -1- (4-hydroxyphenyl) -2-phenylbut Refer to -1-ene. 4-OHT includes the (Z) and (E) isomers as well as their mixtures including racemic and non-racemic mixtures. The (Z) isomer is preferable because it has higher activity than the (E) isomer.

C2 to C6 alcohols are known in the art. Such alcohols include ethanol, propanol, isopropanol (propan-2-ol), n-propanol (propan-1-ol), butanol, butan-1-ol, butan-2-ol, ter-butanol, pentanol, hexanol It includes. Ethanol is preferred because it rapidly evaporates upon contact with skin and effectively contributes to transdermal passage of 4-OHT.

Gelling agents are known in the art. The term "gelling agent" typically refers to a compound having the ability to gel upon contact with a particular solvent, such as water, and may be a polymeric compound. The gelling agent can increase the viscosity of the pharmaceutical composition according to the invention, but can also act as a solubilizer. Examples of gelling agents include acrylic acid based polymers (polyacrylic acid polymers such as CARBOPOL®, manufactured by BF Goodrich Specialty Polymers and Chemicals Division of Cleveland, Ohio), cellulose derivatives, poloxamers and poloxamines, more precisely Is a carbomer or acrylic acid based polymer such as carbopol? 980 or 940, 981 or 941, 1382 or 1382, 5984, 2984, 934 or 934P (carbopol® is usually an acrylic acid polymer crosslinked with allyl sucrose or allylpentaerythritol), Pemulen TR1? Or anionic polymers such as TR2 ?, Ultrez, Synthalen CR and the like; Cellulose derivatives and mixtures thereof such as carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose and the like; Poloxamer or Lutrol? Polyethylene-polypropylene copolymers such as grade 68 or 127, poloxamine; And other gelling agents such as chitosan, dextran, pectin and natural gums. All of the above gelling agents can be used alone or in combination in the pharmaceutical composition according to the invention. Particular preference is given to cellulose compounds comprising carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose and mixtures thereof in the context of the present invention.

Penetration enhancers are also known in the art. "Permeability enhancers" are commonly known as substances that facilitate the delivery of drugs or active ingredients through the skin. Such materials are also referred to as penetration enhancers, auxiliaries and absorption accelerators. This group of substances has the function of improving the solubility and diffusion ability of the drug, and changes the function of the stratum corneum to retain moisture, softens the skin, improves skin permeability, or as a penetration aid or pore opening agent. Materials that have a variety of mechanisms of action, including those that act or temporarily change the condition of the skin, such as the boundary layer, to improve transdermal absorption. The penetration enhancer in connection with the present invention may be an isosteric variant of a fatty acid or a non-acidic derivative of a carboxyl functional group of a fatty acid or a functional derivative of a fatty acid comprising an isosteric variant thereof. In one embodiment, the functional derivative of a fatty acid is unsaturated alkanoic acid in which the —COOH group is substituted with a functional derivative such as alcohols, polyols, amides and substituted derivatives thereof. The term "fatty acid" means a fatty acid having 4 to 24 carbon atoms. Non-limiting examples of penetration enhancers include C8 to C22 fatty acids such as isostearic acid, octanoic acid and oleic acid; C8 to C22 fatty alcohols such as oleyl alcohol and lauryl alcohol; Lower alkyl esters of C8 to C22 fatty acids such as ethyl oleate, isopropyl myristate, butyl stearate and methyl laurate; Di (lower) alkyl esters of C6 to C8 diacids such as diisopropyl adipate; Monoglycerides of C8 to C22 fatty acids such as glyceryl monolaurate; Tetrahydrofurfuryl alcohol polyethylene glycol ether; Polyethylene glycol, propylene glycol; Glycol ethers, including diethylene glycol monoethyl ether; Diethylene glycol monomethyl ether; Alkylaryl ethers of polyethylene oxide; Polyethylene oxide monomethyl ethers; Polyethylene oxide dimethyl ether; Dimethyl sulfoxide; Glycerol; Ethyl acetate; Acetoacetic acid ethers; Pyrrolidone and N-alkylpyrrolidone; Terpene; Hydroxy acid; Urea; essential oil; And mixtures thereof. Preferred examples include isopropyl myristate. All of the above penetration enhancers can be used alone or in combination, for example in combination with two or three other penetration enhancers.

Aqueous vehicles are known in the art. According to another aspect of the invention, the aqueous vehicle comprises, in addition to water, components useful for pH adjustment, for example one or more buffers. Buffers, in particular pharmacologically acceptable buffers, are known in the art. In one aspect, the aqueous vehicle comprises one or more buffers, preferably citrate buffers such as sodium citrate and / or potassium citrate; Tris buffers such as tris maleate; Sorensen type buffers, dibasic or monobasic phosphates, for example buffers selected from the group consisting of phosphate buffers including dibasic or monobasic sodium phosphate buffers.

In another aspect, the pharmaceutical composition of the present invention also includes a base. Advantageously, the base is preferably pharmaceutically acceptable and is preferably selected from the group consisting of triethanolamine, sodium hydroxide, ammonium hydroxide, potassium hydroxide, arginine, aminomethylpropanol or tromethamine and mixtures thereof. If the pH of the pharmaceutical composition is not optimized for transdermal administration, for example, if the gelling agent comprises at least one acrylic acid-based polymer, the base neutralizes the pharmaceutical composition for topical application to human skin. Contributes to. In addition, the base (neutralizing agent) allows the polymer chain to expand optimally while neutralizing the charge and forming the polymer salt. In particular when the gelling agent comprises an acrylic acid-based polymer, the base preferably comprises triethanolamine. In addition, this allows the optimum viscosity of the pharmaceutical composition according to the invention to be achieved. One skilled in the art will know how to select the appropriate amount of said base in the composition to bring the composition to the desired final pH, in particular with respect to the nature of the gelling agent present in the composition and the alcohol content of the composition. For example, when the carbomer and / or alcohol content is high, tromethanamine and / or NaOH can be used as the base in selected amounts to reach the desired final pH in the composition. The base / gelling agent ratio is preferably 10: 1 to 0.1: 1, more preferably 7: 1 to 0.5: 1, even more preferably 4: 1 to 1: 1.

Unless stated otherwise, percentages refer to the weight of each component based on the total weight of the composition. In this specification, the content of alcohol is to reach an absolute alcohol content, for example anhydrous ethanol content.

According to one aspect of the invention, the pharmaceutical composition comprises 4-OHT 0.105 to 0.950%, preferably 0.105 to 0.195%, more preferably 0.105 to 0.185%, more preferably 0.105 to 0.175%, more preferably Is 0.105 to 0.165%, more preferably 0.105 to 0.155%, more preferably 0.105 to 0.145%, more preferably 0.105 to 0.135%, more preferably 0.105 to 0.125%, more preferably 0.107 to 0.119% , More preferably 0.111 to 0.118%, more preferably 0.112 to 0.117%, even more preferably 0.113 to 0.116%, most preferably 0.114 to 0.115%.

According to another aspect, the pharmaceutical composition comprises 4-OHT 0.205 to 0.950%, preferably 0.210 to 0.900%, more preferably 0.215 to 0.800%, even more preferably 0.220 to 0.750%, even more preferably Is 0.220 to 0.700%, even more preferably 0.220 to 0.600%, even more preferably 0.220 to 0.500%, even more preferably 0.220 to 0.400%, most preferably 0.220 to 0.350%.

According to another aspect of the invention, the pharmaceutical composition comprises 40 to 80%, preferably 45 to 75%, more preferably 50 to 75%, even more preferably 55 to 75%, of at least one alcohol, Most preferably from 60 to 75%.

 According to another aspect of the invention, the C2 to C6 alcohol is selected from the group consisting of ethanol, propan-1-ol and propan-2-ol and mixtures thereof. Preferably, the C2 to C6 alcohol includes ethanol.

 According to another aspect of the present invention, the pharmaceutical composition comprises 0.1 to 5.0%, preferably 0.15 to 4.5%, more preferably 0.2 to 4.0%, even more preferably 0.25 to 3.5% of one or more gelling agents. And even more preferably 0.3 to 3.0%, even more preferably 0.4 to 2.5%, even more preferably 0.5 to 2.0%, most preferably about 0.5 to 1.5%.

According to another aspect of the invention, the gelling agent is a cellulose ester and derivative (cellulose derivatives such as carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose, etc.) At least one selected from the group consisting of cellulose compounds, and mixtures thereof. Preferably, the gelling agent is selected from carboxymethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose and mixtures thereof. Most preferably, the gelling agent comprises hydroxypropylcellulose, for example Klucel.

According to another aspect of the invention, the pharmaceutical composition comprises 0.1 to 5.0%, preferably 0.15 to 4.5%, more preferably 0.2 to 4.0%, even more preferably 0.25 to 3.5% of at least one penetration enhancer. And even more preferably 0.3 to 3.0%, even more preferably 0.4 to 2.5%, even more preferably 0.5 to 2.0%, most preferably about 0.5 to 1.5%.

According to another aspect of the invention, the pharmaceutical composition comprises 0.4 to 2.0% of isopropyl myristate, preferably 0.5 to 1.9%, more preferably 0.5 to 1.8%, even more preferably 0.5 to 1.7%, Even more preferably 0.5 to 1.6%, even more preferably 0.5 to 1.5%, even more preferably 0.6 to 1.4%, even more preferably 0.7 to 1.3%, even more preferably 0.8 to 1.2%, Most preferably about 0.9 to 1.1% or 1.0%.

The composition according to the invention may comprise several penetration enhancers.

According to another aspect of the present invention, the pharmaceutical composition comprises 20 to 50%, preferably 20 to 40%, of an aqueous vehicle.

According to another aspect of the invention, the aqueous vehicle preferably comprises at least one buffer, in particular phosphate buffer.

In another aspect of the invention, the pH of the pharmaceutical composition is preferably 7 to 11, more preferably 7.5 to 10.5, even more preferably 8.0 to 10.0, even more preferably 8.5 to 10.0, most preferably About 8.5 to 9.5.

In one embodiment, the present invention

4-OHT 0.205 to 0.950% (0.105 to 0.950% respectively),

At least one C2 to C6 alcohol, preferably 40 to 80% of ethanol,

At least one gelling agent, preferably from 0.1 to 5.0% of hydroxypropylcellulose,

0.1 to 5.0% of at least one penetration enhancer, and

Providing a pharmaceutical composition comprising 20 to 50% of an aqueous vehicle.

In another embodiment, the present invention relates to

4-OHT 0.210 to 0.900% (0.105 to 0.185% respectively),

At least one C2 to C6 alcohol, preferably 40 to 75% of ethanol,

At least one gelling agent, preferably from 0.15 to 4.5% of hydroxypropylcellulose,

0.15 to 4.5% of at least one penetration enhancer, and

Providing a pharmaceutical composition comprising 20 to 40% of an aqueous vehicle.

In another embodiment, the present invention relates to

4-OHT 0.215 to 0.800% (0.105 to 0.165% respectively),

At least one C2 to C6 alcohol, preferably 45 to 75% of ethanol,

At least one gelling agent, preferably from 0.2 to 4.0% of hydroxypropylcellulose,

0.2 to 4.0% of at least one penetration enhancer, and

Providing a pharmaceutical composition comprising 20 to 40% of an aqueous vehicle.

In another embodiment, the present invention relates to

4-OHT 0.220 to 0.750% (0.105 to 0.145% respectively),

At least one C2 to C6 alcohol, preferably 45 to 75% of ethanol,

At least one gelling agent, preferably from 0.25 to 3.5% of hydroxypropylcellulose,

0.25-3.5% of one or more penetration enhancers, and

Providing a pharmaceutical composition comprising 20 to 40% of an aqueous vehicle.

In another embodiment, the present invention relates to

4-OHT 0.220 to 0.700% (0.105 to 0.125% respectively),

At least one C2 to C6 alcohol, preferably 50 to 75% of ethanol,

At least one gelling agent, preferably from 0.3 to 3.0% of hydroxypropylcellulose,

0.3-3.0% of one or more penetration enhancers, and

Providing a pharmaceutical composition comprising 20 to 40% of an aqueous vehicle.

In another embodiment, the present invention

4-OHT 0.220 to 0.600% (0.111 to 0.118% respectively),

At least one C2 to C6 alcohol, preferably 60 to 75% of ethanol,

At least one gelling agent, preferably 0.4-2.5% of hydroxypropylcellulose,

0.4-2.5% of at least one penetration enhancer, and

Providing a pharmaceutical composition comprising 20 to 40% of an aqueous vehicle.

In another embodiment, the present invention

4-OHT 0.220 to 0.500% (0.112 to 0.117% respectively),

At least one C2 to C6 alcohol, preferably 60 to 75% of ethanol,

At least one gelling agent, preferably from 0.5 to 2.0% of hydroxypropylcellulose,

0.5 to 2.0% of at least one penetration enhancer, and

Providing a pharmaceutical composition comprising 20 to 40% of an aqueous vehicle.

In another embodiment, the present invention

4-OHT 0.220 to 0.400% (0.113 to 0.116% respectively),

At least one C2 to C6 alcohol, preferably 60 to 75% of ethanol,

At least one gelling agent, preferably from 0.5 to 1.5% of hydroxypropylcellulose,

0.5 to 1.5% of at least one penetration enhancer, and

Providing a pharmaceutical composition comprising 20 to 40% of an aqueous vehicle.

In another embodiment, the present invention

4-OHT 0.220 to 0.350% (0.114-0.115% each),

At least one C2 to C6 alcohol, preferably 60 to 75% of ethanol,

At least one gelling agent, preferably from 0.5 to 1.5% of hydroxypropylcellulose,

0.5 to 1.5% of at least one penetration enhancer, and

Providing a pharmaceutical composition comprising 20 to 40% of an aqueous vehicle.

In another embodiment, the present invention

4-OHT 0.205 to 0.950% (0.105 to 0.950% respectively),

At least one C2 to C6 alcohol, preferably 40 to 80% of ethanol,

At least one gelling agent, preferably from 0.1 to 5.0% of hydroxypropylcellulose,

Isopropyl myristate 0.4-2.0%, and

Providing a pharmaceutical composition comprising 20 to 50% of an aqueous vehicle.

In another embodiment, the present invention relates to

4-OHT 0.210 to 0.900% (0.105 to 0.185% respectively),

At least one C2 to C6 alcohol, preferably 40 to 75% of ethanol,

At least one gelling agent, preferably from 0.15 to 4.5% of hydroxypropylcellulose,

Isopropyl myristate from 0.5 to 1.8%, and

Providing a pharmaceutical composition comprising 20 to 40% of an aqueous vehicle.

In another embodiment, the present invention

4-OHT 0.215 to 0.800% (0.105 to 0.165% respectively),

At least one C2 to C6 alcohol, preferably 45 to 75% of ethanol,

At least one gelling agent, preferably from 0.2 to 4.0% of hydroxypropylcellulose,

Isopropyl myristate 0.6-1.4%, and

Providing a pharmaceutical composition comprising 20 to 40% of an aqueous vehicle.

In another embodiment, the present invention relates to

4-OHT 0.220 to 0.750% (0.105 to 0.145% respectively),

At least one C2 to C6 alcohol, preferably 45 to 75% of ethanol,

At least one gelling agent, preferably from 0.25 to 3.5% of hydroxypropylcellulose,

Isopropyl myristate 0.5-1.5%, and

Providing a pharmaceutical composition comprising 20 to 40% of an aqueous vehicle.

In another embodiment, the present invention

4-OHT 0.220 to 0.700% (0.105 to 0.125% respectively),

At least one C2 to C6 alcohol, preferably 50 to 75% of ethanol,

At least one gelling agent, preferably from 0.3 to 3.0% of hydroxypropylcellulose,

Isopropyl myristate 0.6-1.4%, and

Providing a pharmaceutical composition comprising 20 to 40% of an aqueous vehicle.

In another embodiment, the present invention

4-OHT 0.220 to 0.600% (0.111 to 0.118% respectively),

At least one C2 to C6 alcohol, preferably 60 to 75% of ethanol,

At least one gelling agent, preferably 0.4-2.5% of hydroxypropylcellulose,

Isopropyl myristate from 0.7 to 1.3%, and

Providing a pharmaceutical composition comprising 20 to 40% of an aqueous vehicle.

In another embodiment, the present invention

4-OHT 0.220 to 0.500% (0.112 to 0.117% respectively),

At least one C2 to C6 alcohol, preferably 60 to 75% of ethanol,

At least one gelling agent, preferably from 0.5 to 2.0% of hydroxypropylcellulose,

Isopropyl myristate 0.8 to 1.2%,

Providing a pharmaceutical composition comprising 20 to 40% of an aqueous vehicle.

In another embodiment, the present invention

4-OHT 0.220 to 0.400% (0.113 to 0.116% respectively),

At least one C2 to C6 alcohol, preferably 60 to 75% of ethanol,

At least one gelling agent, preferably from 0.5 to 1.5% of hydroxypropylcellulose,

Isopropyl myristate 0.9 to 1.1%, and

Providing a pharmaceutical composition comprising 20 to 40% of an aqueous vehicle.

In another embodiment, the present invention relates to

4-OHT 0.220 to 0.350% (0.114 to 0.115%, respectively),

Ethanol 60-75%,

Hydroxypropyl cellulose from 0.5 to 1.5%,

Isopropyl myristate 0.4-2.0%, and

Providing a pharmaceutical composition comprising 20 to 40% of an aqueous vehicle.

In addition, the pharmaceutical composition may comprise conventional pharmaceutical additives including salts, softeners, stabilizers, antimicrobial agents, fragrances and / or propellants. The pharmaceutical composition may also comprise one or more additional active ingredients.

The present invention also provides a gel useful for transdermal or transdermal delivery comprising the pharmaceutical composition according to the present invention. Accordingly, the present invention relates to hydro-alcoholic gels containing 4-OHT.

According to another embodiment, the present invention provides a dose packet, unit dose packet or multiple dose packet containing the pharmaceutical composition or hydroalcoholic gel. Advantageously, such conditioning of the pharmaceutical composition allows the patient to administer more conveniently. Thus, this package form may reflect a dosing schedule, for example daily or weekly dosing.

According to another embodiment, a dispenser (dispenser) containing the pharmaceutical composition or the hydroalcoholic gel is provided, for example a dispenser with a hand pump or valve. Such dispensers facilitate adjustment in the dosage as a function of the amount of the composition to be applied.

According to one embodiment, the packet or dispenser may be accompanied by instructions for use.

The pharmaceutical compositions, gels, packets and containers of the present invention are useful for treating a variety of symptoms and / or diseases.

The term “treat” or “treatment” as used herein includes treating a symptom, disease or condition of a mammal, including predisposition to such condition, disease or condition but not yet diagnosed. To prevent their development, for example, to stop the progression of a symptom, disease or condition and to inhibit such symptoms, disease or condition, for example to cause regression of the condition, disease or condition such as Alleviating the symptoms, disease or condition, or stopping the symptoms of the disease or condition to alleviate the symptoms manifested by such disease or condition.

“Prevent” or “prevention” in connection with a symptom, disease or condition means that such condition, disease or condition is not present if the condition, disease or condition has not occurred, or that the condition, disease or condition has already occurred , Means that the disease or condition is no longer advanced.

In particular, the pharmaceutical compositions, gels, packets and containers of the present invention are useful for the following uses:

Treatment and / or Prevention of Diseases Associated with Dense Breast Tissue Highly dense breast tissue is a predictor of breast cancer risk and reduces sensitivity to breast imaging devices, which is an important issue in the detection and diagnosis of cancer. The dense breast tissue may be diffuse or nodular.

Treatment and / or Prevention of Benign Breast Disease Benign breast disease generally refers to common non-malignant variations of breast tissue. Such mutations include numerous lesions with well-defined histological properties and can be classified as proliferative or non-proliferative. Representative benign breast diseases that can be treated by current methods include adenosis, cysts, ductal dilatation, fibroadenomas, fibrosis, hyperplasia, metaplasia and other fibrocystic changes. Such diseases are often referred to as "changes" or "symptoms" in view of their morbidity and have well-defined histological and clinical characteristics. "Goodness" is a generalized mammary disease. This typically involves the enlargement of breast lobules that contain more than usual glands. In "sclerotic adenomas" or "fibrotic adenomas", enlarged lobules are modified by scary fibrous tissue. A "cyst" is an abnormal cyst resulting from the lobular structure, filled with body fluids or semisolid material and whose inner surface is a mammary epidermal cell. The cyst starts from excess fluid inside the mammary gland, but can grow into areas that extend and surround breast tissue, causing pain. A "fibrocystic" is a cyst gland lesion that is within or surrounded by a significant amount of fibrous connective tissue. "Gynecodilator" refers to the expansion of the ducts by lipid or cellular debris. Rupture of the canal leads to infiltration by granulocytes and plasma cells. "Fiber adenoma" refers to benign tumors derived from the glandular epidermis and contains a significant amount of proliferative fibroblast matrix and connective tissue. "Fibrosis" simply means the elevation of fibrous tissue in the breast. Hyperplasia refers to the phenomenon of overgrowth of cells in which layers of cells cover the inner surface of the basement membrane without tumor formation. Hyperplasia increases the volume of breast tissue. In "epidermal hyperplasia", the cells surrounding the inner surface of the canal and lobules are related and are referred to as "ductal hyperplasia" and "lobular hyperplasia". Based on histological measurements, hyperplasia can be characterized as "typical" or "typical.""Velogen" refers to the conversion of one type of differentiated tissue into another type of differentiated tissue. Metabolism often results from environmental changes and allows cells to tolerate such changes better.

Treatment and / or prophylaxis of scars, including excessive scars, keloid scars and hypertrophic scars "Excessive scars" or "Excessive scar formations" generally lead to overgrowth of dense fibrous tissue resulting from abnormal wound healing. Excessive scars grow larger than needed for normal wound healing and are characterized by an overproduction of cells, collagen and / or proteoglycans. "Keloid scars" are dense fibrous tissue that extends beyond the boundaries of the original wound or incision, usually leading to excessive scars that do not spontaneously recover. Since keloids are often apparently similar to other hypertrophic scars, it can be difficult to determine whether the scar is a keloid. However, keloids have histological features that distinguish them from others. Such a feature is collagen nodules, which contain highly organized and distinct directional dense fibroblasts and unidirectional collagen fibrils. In addition, keloids have abundant vascular structure, high mesenchymal cell density and thickened epidermal cell layers. "Homegaly scars" are excessive scars where dense fibrous tissue does not extend beyond the boundaries of the original wound or incision. Hypertrophic scars tend to be produced in a wider range than necessary for normal wound healing to occur. Histologically, hypertrophic scars have more collagen fibers than keloids and have an inadequate mucus matrix. Hypertrophic lesions consist of extracellular matrix and cells oriented in a single axis and are characterized by irregularly distributed tissue bundles.

- the treatment of gynecomastia gynecomastia in young boys and adult males is benign and sometimes as general symptoms indicating the growth of breast tissue that is painful, gihayeo the underlying disease should also appear as secondary.

Prevention and / or treatment of breast cancer, in particular non- invasive breast cancer

- Treatment of yubangtong yubangtong or breast pain is the most common breast problem for women to get regular medical doctors. The pain levels vary, but breast pain is very persistent and intense, which interferes with normal daily activities or, in severe cases, makes the body unusable due to pain. Breast pain can be classified according to three general aspects of pain: (1) periodic breast pain, (2) non-periodic breast pain, and (3) extramammary pain. Periodic breast pain is caused by physiological breast hypertrophy caused by estrogen-dependent vascular changes during the luteal phase of the menstrual cycle and affects the majority of premenopausal women. Periodic breast pain may also recur with a dose-dependent effect in postmenopausal women who receive female hormone replacement therapy. "Non-periodic breast pain" refers to pain in the breast that is not associated with the menstrual cycle, as its name suggests. Many diseases, including sclerosis, Tiez's syndrome and rarely breast cancer, cause non-periodic breast pain. Finally, extramammary pain includes breast pain projected into the breast from another source, such as occurs when a patient feels pain from muscles or ribs below the breast.

Pharmaceutical compositions and gels of the present invention may be used in "combination therapy" with additional active agents.

In another aspect, the invention also relates to the use of a gel or solution according to the invention for the preparation of a medicament for transdermal administration for the treatment of one or more of the above-mentioned indications.

In another aspect, the present invention relates to a method of treatment.

In one embodiment, the method includes a method of topically administering 4-OHT to a patient.

According to one aspect, the pharmaceutical composition or gel of the present invention may be applied on one or both breasts or scars depending on the indication.

4-OHT dosages can be adjusted by one skilled in the art. When applied to breast skin, 0.50 to 3.0 mg / day / breast, preferably 0.60 to 2.5 mg / day / breast, more preferably 0.75 to 2.3 mg / day / breast, even more preferably 1.0 to 2.0 mg / day / breast. Ideally, the unit dose of the composition (gel) is from about 0.5 to about 3.5 g, which is a weak range in which the gel of the present invention exhibits a pharmacodynamic linear proportional function relationship. If it exceeds 3.5 g, it has been found that patient suitability is limited in addition to pharmacodynamic variability. In addition, below about 0.5 g, there is a pharmacodynamic non-linear relationship. More preferably, the unit dose of the gel may be greater than about 0.75 g, or greater than about 1 g.

In the case of scars, the dosage may be 0.25 to 3.0 μg / cm ² , preferably 0.5 to 2.5 μg / cm ² , more preferably 1.0 to 2.0 μg / cm ² .

The pharmaceutical compositions and methods of the present invention are useful for patients, especially women, in that they have a convenient and reproducible suitability, especially when high doses are involved. With regard to high doses, the present invention means at least 1 mg of 4-OHT, preferably at least 2 mg of 4-OHT.

To deliver such high doses of 4-OHT, the actual amount of gel delivered to the patient is more appropriate regardless of the skin surface area (eg, breast size) applied. In other words, patient compatibility will generally not depend on the area of skin to which it is applied (eg, the size of the breast or scar). On the other hand, in other less concentrated formulations, the dose actually delivered to the patient will depend on the area of skin to be applied, thus jeopardizing proper suitability.

In another aspect, the present invention provides a method for preparing the pharmaceutical composition or gel according to the present invention.

In one aspect, the method includes preparing a mixture containing at least one C2 to C6 alcohol and at least one penetration enhancer.

In another aspect, the method includes adding and mixing the desired amount of 4-OHT.

In another aspect, the method includes adding and mixing one or more gelling agents.

In another aspect, the method includes adding and mixing one or more aqueous vehicles.

In another aspect, the method

Preparing a mixture containing at least one C2 to C6 alcohol and at least one penetration enhancer;

Adding and mixing the desired amount of 4-OHT;

Adding at least one gelling agent and mixing again; And

Adding at least one aqueous vehicle and mixing again.

Those skilled in the art are familiar with these steps and the corresponding techniques and will therefore know how to proceed to implement the method.

The advantages of the invention will be apparent from the following examples given for the purpose of mere illustration, but the invention is not so limited.

Those skilled in the art will recognize that the present invention may incorporate various preferred features described above.

All cited references mentioned herein are incorporated herein in their entirety. Other embodiments of the invention that are apparent to those skilled in the art are not described herein but are within the scope and spirit of the invention. The present invention uses common pharmacological and pharmaceutical techniques known in the art, unless otherwise noted.

Example

Example  1: Preparation of pharmaceutical composition (gel)

Various pharmaceutical compositions were prepared:

 EP: European Pharmacopoeia; USP: US Pharmacopoeia

The 4-OHT containing composition was prepared in a multistep mixing process. In general, the penetration enhancer (isopropyl myristate in this example) and the alcohol (ethanol in this example) were mixed. Desired amount of 4-OHT was added and mixed and then combined with hydroxypropylcellulose (Klucel HF). At the end of the process, the formulation was mixed with an aqueous vehicle (in this example, a buffered aqueous solution). The final product was transferred to a vessel / sealing system by a turbine. Because the drug is sensitive to light, the step involving the drug was performed under non-chemical light.

Preparation of aqueous phosphate buffer (pH 7) : To prepare 1000 g of pH 7 aqueous buffer, 0.85 g of KH ₂ PO ₄ and 3.46 g of Na ₂ HPO ₄ were weighed and diluted with 1000 g of purified water. The solution was mixed in a portable mixer for at least 10 minutes.

The primary mixing tank was checked to ensure that the proper cleaning process was carried out.

Alcohol was added to the mixing tank under 800 mbar vacuum without mixing.

The tank was filled with isopropyl myristate. The excipient container was washed with alcohol.

Turn on non-chemical light, turn off room lighting.

4-OHT was placed in the mixing tank and the vessel was rinsed with alcohol.

The solution was mixed for 20 minutes at 2,000 rpm for the turbine and 40 rpm for the scraper.

*-The mixing tanks were charged with hydroxypropylcellulose (Clucell HF) under a turbine 2,000 rpm, 800 mbar vacuum. The turbine was stopped at the end of the process.

The materials were mixed for 20 minutes in an alternating manner as follows:

20 seconds at 2,000 rpm and 20 seconds at 600 rpm with turbine

* 40 rpm / min with scraper

The turbine was stopped at the end of the process.

Phosphate buffer was transferred to the mixing tank under scraper 40 rpm, 800 mbar vacuum.

The product was mixed for 20 minutes in an alternating manner as follows:

20 seconds at 2,000 rpm and 20 seconds at 600 rpm with turbine

* 40 rpm / min with scraper

The turbine was stopped at the end of the process.

The mixing tank was slowly brought to 100 mbar vacuum.

* Step 1: 250 mbar

Step 2: 150 mbar

Step 3: 100 mbar

Scraper 40 rpm was maintained at 100 mbar vacuum for 2 minutes.

The product was mixed at scraper 40 rpm for 10 minutes. The scraper was stopped at the end of the process.

To prevent the incorporation of additional air, the gel was transferred to a capped stainless steel tank via an extraction turbine.

Sampling was performed during the transfer process.

The gel thus obtained was stable, colorless and transparent or slightly opaque.

Example  2: In vitro  Absorption test

Materials and methods

4- OHT  Gel

Radiolabeled 4-OHT ( ³ H) was used in the preparation of pharmaceutical compositions as described above. A composition (gel) containing 4-OHT at concentrations of 0.057%, 0.114% and 0.228% was prepared.

In vitro  Skin absorption:

principle

In vitro transdermal absorption was quantitatively experimented with excised human abdominal skin biopsies placed on static diffuse cells (Franz cells), allowing the dermis to come into contact with the remaining liquid (liquid in the container) which becomes the absorbed dose through the skin.

cell

Skin biopsies are held horizontally between two parts of the cell and bounded by two zones as follows:

-The epidermal zone is located above the skin and is exactly 1.77 cm ² It consists of a glass cylinder of an area.

The other is the dermal zone corresponding to the lower surface of the skin, consisting of a fixed volume reservoir with a side collection port.

Two elements were collected via clamps.

The lower section (dermis) was filled with a receptor liquid consisting of 9 g / L sodium chloride solution supplemented with 15 g / L bovine serum albumin.

At each time point, the remaining liquid was sampled completely through the side collection port and replaced with fresh liquid.

The lower part of the cells was fixed at 37 ° C. The temperature of the receiver liquid and the uniformity of the components were maintained by stirring (magnetic stirrer).

Since the top (epidermal compartment) is open outwards, the epidermal surface is exposed to the laboratory atmosphere.

Preparation of a dermis biopsy excised from the human abdomen :

Biopsies were sampled from human abdominal skin through plastic surgery from a white donor. The skin was stored at -20 ° C before use. Sticky subcutaneous fat was removed with a surgical scalpel and divided to a thickness of about 0.5 mm using a skin excision. For each test formulation and each volume, 12 Franz cells were prepared and 3 different donor skin samples were evenly distributed across 12 cells.

General protocol

Franz cells were usually prepared the day before loading the formulation for testing. The epidermal zone was in contact with the laboratory atmosphere, the dermal zone was heat set at 37 ° C. and the skin was contacted with albuminated physiological serum for about 17 hours.

The desired amount of gel (5 μl, 10 μl or 20 μl) was applied by micropipette to all of the surface of the epidermis delimited by a glass cylinder. Sampling from the liquid contained in the dermal zone was performed through the lateral collection port at the 24 hour time point.

Radioactivity measurement

Detection was performed by liquid scintillation using a particle counter Packard-tricarb 2900 TR.

Preparation of radioactive samples :

Receptor liquids sampled from the lower zone of the diffuse cells for radioactivity measurements were incorporated directly into 15 mL of liquid scintillation cocktail (Picofluor 40R) and measured.

Radioactivity Measurement :

To obtain the number of decays per minute (dpm) representing the actual activity of each sample, the measurement rate was extrapolated as far as quenching was concerned. The background was subtracted from cpm for each sample. For each scintillation liquid, a specific quench curve was established. The results are expressed as weight or percent of material found in the sample relative to the dose administered, determined from the measurement of the appropriately diluted calibration.

protocol

For a given concentration of 4-0HT in the composition and a given volume of the composition applied on the skin, an average result, corresponding to 11-12 experimental measurements, is expressed as the standard deviation (Sd).

result

In vitro Franz  4- into cells OHT Penetration

At the 24-hour time point, the mean value ± standard deviation (Sd) of the 4-OHT amount in the receiver liquid:

For example, in the table above, “114 mg / 10 μl” was applied with 10 μl of the gel formulation on the skin surface of 1.77 cm ² , and the gel formulation was 114 mg (4-OHT 0.114 4-OHT per 100 g of gel). %).

The results show that when the same amount of 4-OHT is applied, the amount of 4-OHT absorbed is much better controlled in 0.114% and 0.228% formulations than in 0.057% formulations:

For the 0.057% formulation, when the applied volume was increased 4 times (from 5 μl to 20 μl), the percent absorption increased unexpectedly by about 5 times. This resulted in a 23.5-fold increase in 4-OHT uptake, even though the application amount of 4-OHT was increased only four-fold (increasing the coating volume from 5 to 20 μl). In other words, when increasing the application amount of 4-OHT by 4 times, the amount actually absorbed increases by 23.5 magnification. In conclusion, in 0.057% formulation, there is a large variation in the amount of 4-OHT absorbed, and the extent of absorption is not linearly proportional to the volume applied. This effect is surprisingly reduced in 0.114% and 0.228% formulations.

For example, in a 0.228% formulation, if the application volume is increased fourfold (from 5 μl to 20 μl), the 4-OHT uptake percentage increases less (about three times), and the amount of 4-OHT absorbed is only 16.6 times increase.

This feature is particularly advantageous when the composition of the present invention is applied onto the breast:

The experiment showed that the amount of 4-OHT absorbed changed as a function of volume to a lesser extent in 0.114% and 0.228% formulations compared to 0.057% formulations.

The experiments were all performed on the same skin surface area (1.77 cm ² ). Thus, this protocol (variably varying the applied gel volume for the same surface area) reflects what happens when applying the same amount of gel for various surface areas. This is certainly a problem when the formulation is applied on the breast surface.

Advantageously, the compositions of the present invention have improved patient suitability. In order to apply the same therapeutic dose (high dose), administration of 0.228% and 0.114% formulations reduces the amount of formulation and / or gel to be applied, thus allowing administration once daily instead of twice daily. As might be expected, application of the same amount of 4-OHT (with 10 μl of 0.114% formulation or 5 μl of 0.228% formulation) showed similar amounts of 4-OHT absorbed (34 ± 24 vs 20 ± 14; p> 0.05, Mann Whitney). However, when applying a large volume of 0.057% formulation as described above, the absorption was seen to be non-linearly increased, indicating that 4-OHT was the same using 20 μl of 0.057% formulation or 10 μl of 0.114% formulation. When applied in amounts, the amount of 4-OHT absorbed is significantly different (74 ± 35 vs 34 ± 24; p = 0.004, top Whitney); Likewise, when applying the same amount of 4-OHT using 20 μl of 0.057% formulation or 5 μl of 0.228% formulation, the amount of 4-OHT absorbed is significantly different (74 ± 35 vs. 20 ± 14; p = 0.001, top Whitney). Therefore, patients with small breasts had a 0.057% formulation with a thick layer (Franz cells 1.77 cm ^2). Equivalent to 20 μl of sugar), it can be seen that the same formulation is overexposed as compared to patients administered on the same large amount of skin surface area. As such, the formulations according to the invention provide improved patient suitability, so it is advantageous for patients with small breasts to use the formulations according to the invention.

Example  3: In vivo  Absorption experiment

protocol

This experiment is an open study in which 32 healthy women with regular menstrual cycles received various doses of 4-OHT. Women are randomly assigned to one of the doses (1 daily dose is 1 mg 4-OHT for group A and B, 2 mg 4-OHT for group C, 4 mg 4-OHT for group D), 21 It was applied to the breast every morning in succession for days.

4-OHT as 0.228% w / w hydroalcoholic gel (daily dose experiment of 4-OHT: 1 mg (Group B) or 4 mg (Group D)) as described in Example 1 or 0.057% w / w hydroalcoholic gel (daily dose experiment of 4-OHT: 1 mg (Group A) or 2 mg (Group C)).

Time to reach maximum blood concentration (t _max ), maximum blood concentration (C _max ), up to 24 hours, until the last measurement of blood concentration (AUC _{0 -24} and AUC _tlast ) and extrapolated to infinity (AUC _0-∞ The area under the time versus blood concentration curve was assessed on the last day of dosing (day 21).

result

After multiple administrations of 4-OHT at 1 mg, 2 mg and 4 mg each, the condition always reached between 14 and 20 days.

The maximum concentration after the last dose was 12.8, 1 on average, for the 1 mg (0.057% gel), 1 mg (0.228% gel), 2 mg (0.057% gel) and 4 mg (0.228% gel) administration groups, respectively. 6.0, 11.8 and 3.5 hours were reached. However, the individual t _max values are very variable and range from 0 to 24 hours. The high variability of t _max reflected a flat concentration time profile (no apparent peak concentration).

To the C _max (pg / ml) and _{AUC 0 -24 (pg * hr /} ml) it is shown in the following Table.

 Gel 0.057% = 0.057% 4-OHT containing gel

 Gel 0.228% = 0.228% 4-OHT containing gel

This result can be explained as follows:

The uptake of 4-OHT (expressed in AUC) is dose-proportional between the 2 mg and 4 mg doses, given the variability (see results for group C vs. D). Because of the large amount of gel (7 g on both breasts), it is not possible to apply a daily dose of 4 mg in a daily dose of 0.057% gel, while advantageously 0.228% gel has the appropriate amount of gel, and lower concentration Absorption (2810 pg * hr / ml, Group D) similar to the theoretical absorption (2 * 998 pg * hr / ml, twice absorption for Group C) of the gel was provided. This is consistent with the in vitro results and indicated that for appropriate amounts of gel (10 and 5 μl), similar 4-OHT uptake can be achieved between gels (absorption is proportional to dose).

Although dose proportionality was observed above, there was unexpectedly no linear proportion between 1 mg and 4 mg 4-OHT doses for 0.228% gel (2810 pg * hr / ml divided by 4 ≠ 383 pg * hr / ml; see results from group B versus group D: although group D dose is four times that of group B, absorption in group D is not four times that of group B). This is consistent with in vitro data showing the effect of gel capacity on absorption, and demonstrated that excess gel affects absorption in a non-linear manner. However, in this case the amount of gel applied on the breast was not excessive, so this in vivo data provided unexpected results with very small amounts (0.44 g) of gel.

The conclusion of the results is that the absorption for the same 1 mg therapeutic dose in two gels (0.057% and 0.228%) applied over a defined area (breast) is not similar. This is gel / cm²Increasing the amount of 4 by 4 means significant impact on absorption. This was surprising because very contradictory results were observed in very similar gels containing testosterone instead of 4-OHT and were completely unexpected. That is, a testosterone gel of a given dose is applied at 1 site to 4 sites and then 4 times gel / cm² The dose change did not significantly affect testosterone absorption [Wang C et al, "Pharmacokinetics of transdermal testosterone gel in hypogonadal men: application of gel at one site versus four site: a general clinical research center study, "The Journal of Clinical Endocrinology & Metabolism, 2000, vol 85, n^o3, p964-969).

Claims (1)

As weight percent based on the total weight of the composition, 0.220 to 0.350% 4-hydroxy tamoxifen; Ethanol 60-75%; Hydroxypropylcellulose 0.5-1.5%; Isopropyl myristate 0.4-2.0%; And administering a pharmaceutical composition comprising 20 to 40% of a phosphate buffer.